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Significance

Although millions of procedures are performed under general anesthesia every year, we do not fully understand the mechanisms underlying anesthesia. Orexin neurons in the hypothalamus form one of the centers in the central nervous system involved in sleep–wake control. The orexin system has also been implicated in anesthesia. In this study, we specifically activated orexin neurons via a designer receptor that is exclusively activated by a designer drug, to test how activation of orexin neurons affects anesthesia recovery. We found that orexin neuronal activation can speed up wakeup and improve pain control as well. Our study suggests that the orexin system has the potential as a target for drug discovery to facilitate postprocedural recovery.

Abstract

Orexin (also known as hypocretin) neurons in the hypothalamus play an essential role in sleep–wake control, feeding, reward, and energy homeostasis. The likelihood of anesthesia and sleep sharing common pathways notwithstanding, it is important to understand the processes underlying emergence from anesthesia. In this study, we investigated the role of the orexin system in anesthesia emergence, by specifically activating orexin neurons utilizing the designer receptors exclusively activated by designer drugs (DREADD) chemogenetic approach. With injection of adeno-associated virus into the orexin-Cre transgenic mouse brain, we expressed the DREADD receptor hM3Dq specifically in orexin neurons and applied the hM3Dq ligand clozapine to activate orexin neurons. We monitored orexin neuronal activities by c-Fos staining and whole-cell patch-clamp recording and examined the consequence of orexin neuronal activation via EEG recording. Our results revealed that the orexin–DREADD mice with activated orexin neurons emerged from anesthesia with significantly shorter latency than the control mice. As an indication of reduced pain sensitivity, these orexin–DREADD mice took longer to respond to the 55 °C thermal stimuli in the hot plate test and exhibited significantly less frequent licking of the formalin-injected paw in the formalin test. Our study suggests that approaches to activate the orexin system can be beneficial in postoperative recovery.

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